Journal of Clinical Medicine Review Reproductive Chances of Men with Azoospermia Due to Spermatogenic Dysfunction Caroline Kang † , Nahid Punjani † and Peter N. Schlegel * Department of Urology, Weill Cornell Medical College, New York, NY 10021, USA; [email protected] (C.K.); [email protected] (N.P.) * Correspondence: [email protected] † Equal contribution. Abstract: Non-obstructive azoospermia (NOA), or lack of sperm in the ejaculate due to spermato- genic dysfunction, is the most severe form of infertility. Men with this form of infertility should be evaluated prior to treatment, as there are various underlying etiologies for NOA. While a significant proportion of NOA men have idiopathic spermatogenic dysfunction, known etiologies including ge- netic disorders, hormonal anomalies, structural abnormalities, chemotherapy or radiation treatment, infection and inflammation may substantively affect the prognosis for successful treatment. Despite the underlying etiology for NOA, most of these infertile men are candidates for surgical sperm retrieval and subsequent use in intracytoplasmic sperm injection (ICSI). In this review, we describe common etiologies of NOA and clinical outcomes following surgical sperm retrieval and ICSI. Keywords: non-obstructive azoospermia; infertility; intracytoplasmic sperm injection Citation: Kang, C.; Punjani, N.; 1. Introduction Schlegel, P.N. Reproductive Chances of Men with Azoospermia Due to Infertility affects up to 15% of couples worldwide, with up to 50% of cases attributable Spermatogenic Dysfunction. J. Clin. to male factor infertility [1]. In a majority of cases, the precise etiology underlying infertility Med. 2021, 10, 1400. https://doi.org/ in the male partner remains unclear. A subset of men with infertility have no sperm in 10.3390/jcm10071400 the ejaculate, known as azoospermia, which may further be classified into obstructive (OA) or non-obstructive azoospermia (NOA). The majority of cases of NOA are idiopathic, Academic Editors: Giovanni M. Colpi however some known etiologies include genetic disorders, chemotherapy or radiation, and Ettore Caroppo developmental or structural abnormalities, and hormonal imbalances (Table1). Despite the etiology underlying the spermatogenic dysfunction resulting in NOA, sperm often Received: 4 March 2021 can be surgically extracted from the testis for use in assisted reproductive technology Accepted: 26 March 2021 (ART) with varying success. Intracytoplasmic sperm injection (ICSI) requires only a single Published: 31 March 2021 spermatozoon for injection into an oocyte, and thus has improved the chances for men with NOA to conceive biological children. In this review, we discuss common etiologies for Publisher’s Note: MDPI stays neutral NOA and the reproductive outcomes for NOA men after surgical sperm retrieval and ICSI. with regard to jurisdictional claims in published maps and institutional affil- Table 1. Etiologies of non-obstructive azoospermia. iations. Etiology Example Idiopathic Genetic/Chromosomal Klinefelter syndrome, Y-chromosome microdeletions Iatrogenic/Surgical Chemotherapy, Radiation therapy Copyright: © 2021 by the authors. Developmental/Structural Cryptorchidism/Orchidopexy, Varicocele Licensee MDPI, Basel, Switzerland. Kallmann syndrome, hypogonadotropic Hormonal This article is an open access article hypogonadism, hyperprolactinemia/prolactinoma distributed under the terms and conditions of the Creative Commons 2. Treatment of Non-Obstructive Azoospermia Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ Effective management of infertility in men with NOA requires testicular sperm re- 4.0/). trieval as well as ART in the form of ICSI. Since sperm retrieval involves finding one of J. Clin. Med. 2021, 10, 1400. https://doi.org/10.3390/jcm10071400 https://www.mdpi.com/journal/jcm J. Clin. Med. 2021, 10, 1400 2 of 18 the very limited sites of sperm production within a highly dysfunctional testis of a man with NOA, it is not surprising that the approach used for sperm retrieval can substantially affect the chance of obtaining sperm for fertility. A wide variety of approaches have been used for attempted sperm retrieval including fine needle aspiration of the testis (testicular sperm aspiration; TESA), random biopsies of testicular tissue to identify foci of sperm production (testicular sperm extraction; “conven- tional” TESE) as well as directed testicular surgical sperm retrieval using a microsurgical approach (microdissection testicular sperm extraction; microTESE or mTESE). Each of these methods were compared using a meta-analysis of published litera- ture [2]. Although a recent meta-analysis reported no difference in sperm retrieval rates when comparing conventional TESE to microTESE, it is important to note that this anal- ysis did not require comparative studies so the heterogeneous nature of NOA patients treated at different sites invalidated any meaningful comparison of surgical techniques [3]. The superiority of microTESE is not surprising, as the surgery directs sampling of testicular tissue to the largest seminiferous tubules, which are those most likely to contain sperm [4]. From a laboratory perspective, the microTESE approach is ideal, as it limits the amount of tissue that must be examined by the andrologist to identify sperm to that which is richest in sperm production. Typical search times to find sperm in isolated, dispersed testicular tissue specimens is only 3 to 5 min at experienced centers. Of note, microTESE, although an invasive surgical procedure, has less effect on testicular function than other approaches for sperm retrieval [4]. 3. Causes of Non-Obstructive Azoospermia NOA occurs secondary to the disruption of spermatogenesis within the testicular parenchyma. This disruption of sperm production is a common phenotype with various underlying etiologies. Although understanding the underlying etiology of azoospermia may help in prognosis and counseling, the precise mechanisms by which spermatogenesis is disrupted in these disorders are not well understood. Men with NOA have varying ranges of spermatogenic failure, and even in 30–60% of those with severely dysfunctional histology (i.e., Sertoli Cell Only (SCO) or maturation arrest) small foci of spermatogenesis can be observed [5]. Furthermore, many other presumed idiopathic cases of NOA are likely to be caused by genetic abnormalities that are yet to be fully delineated. 3.1. Hormonal Imbalances Men with hypogonadotropic hypogonadism (HH) suffer from a lack of gonadotropin stimulation, resulting in failure of the testis to produce testosterone or sperm. The defect can be congenital (e.g., Kallmann syndrome, Prader-Willi syndrome) or acquired (e.g., sec- ondary to pituitary tumor or exogenous steroid administration). The resultant phenotype of these men is lack of development of secondary sexual characteristics (with prepubertal phenotype) and infertility. Importantly, because the phenotype is caused by a lack of go- nadotropin, treatment of these men with exogenous gonadotropins (e.g., human chorionic gonadotropin (hCG) and recombinant follicle-stimulating hormone (FSH)) can result in the appropriate development of secondary sexual characteristics (i.e., pubic hair development, testis growth, development of muscle mass) and sperm [6]. Men with HH typically do not require ICSI to achieve pregnancy as treatment with exogenous gonadotropins is highly effective in inducing spermatogenesis adequate to allow return of sperm to the ejaculate, which is associated with an increase in endogenous testosterone production [6]. Hyperprolactinemia, or elevated serum prolactin levels, is a rare etiology for azoosper- mia but clinically relevant. Prolactin is produced by the posterior pituitary and elevated levels can result from a prolactin-secreting adenoma (or prolactinoma) [7]. One study examining prolactin levels in infertile men observed increased prolactin levels in men with asthenozoospermia, oligozoospermia, and azoospermia [8]. Since hyperprolactinemia is typically effectively treated with medical therapy, it is rarely a cause for persistent NOA requiring surgical intervention. J. Clin. Med. 2021, 10, 1400 3 of 18 3.2. Klinefelter Syndrome Klinefelter Syndrome (KS) is the most common sex chromosome aneuploidy in in- fertile men, with an estimated prevalence of approximately 10% in men with NOA [9]. This syndrome involves the addition of one or more extra X-chromosome(s), resulting most commonly in a 47,XXY karyotype [9–11]. KS is thought to occur secondary to chro- mosomal nondisjunction during meiosis [12,13]. Physical examination of KS men often reveals characteristic findings of tall stature, reduced testis size, reduced chest and facial hair, gynecomastia, eunuchoid appearance, wide hips, and narrow shoulders [13]. Small testis size is thought to occur due to fibrosis and hyalinization of the seminiferous tubules and is progressive through puberty and adult development [14,15]. Rare, small foci of spermatogenesis in the testes of KS men is hypothesized to be present due to the capability of XXY stem cells to undergo spermatogenesis, or more likely, mitotic errors within the XXY stem cell population resulting in diploid cells capable of completing the remaining spermatogenic process [16]. 3.3. Y-Chromosome Microdeletions One of the most common identifiable etiologies of NOA are microdeletions of the azoospermia factor (AZF) region of the Y chromosome, and up to 12% of men with NOA harbor AZF microdeletions [17]. There are three